The largest prospective warfarin-treated cohort supports genetic forecasting

Abstract

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P ‫؍‬ 6.63 ؋ 10 ؊34 ) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P ‫؍‬ 9.82 ؋ 10 ؊100

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…17 A review by Schelleman et al 18 illustrates the large number of CYP2C9*2 and *3 allele frequency studies that have focused on populations of European ancestry, in which these genetic variants are common. Together they have been found to account for 12 10 to 18% 6 of the variation in warfarin dose. Recent research has identified a third gene, CYP4F2 as influencing an individual's sensitivity to warfarin.…”

“…Genetic factors have also been shown to affect warfarin maintenance. 3,10 Previous studies have demonstrated that two genes, VKORC1 and CYP2C9, which are involved in the vitamin K-dependent clotting pathway, explain an additional 30-54% of variance observed in warfarin dosing. 6,9,11 Warfarin exists as a mixture of two stereoisomers, R and S. 8,12 S-warfarin is approximately three times as active as the R-enantiomer 12 and works by antagonizing the vitamin K-dependent clotting pathway.…”

“…13 Within the VKORC1 gene, the single nucleotide polymorphism (SNP) rs9923231 has been extensively studied among European and Asian populations. Original research by Wadelius 10 showed that VKORC1 predicts 30% of the variance observed in warfarin dose. Another critical gene is CYP2C9, which codes for the isoenzyme responsible for metabolizing S-warfarin.…”

“…Replacing the fixed dose approach, multiple regression models and various dosing algorithms, which incorporate VKORC1 and CYP2C9 variants along with clinical and environmental information have been developed and successfully explain anywhere from 53-65% of variation in warfarin dose among Europeans and Asians. 7,10,19,25,27 In general, there has been reduced success in groups, such as African Americans, in which dosing algorithms have only explained up to 36% of the variation in warfarin dose. 28 This has been attributed to greater genetic diversity among people of African ancestry and the possible influence of other variants in the VKORC1 and CYP2C9 genes.…”

Idiosyncratiques et « omiques » peuvent-ils rimer ?

“…Il faut donc définir la dose à l'équilibre pour chaque patient afin d'obtenir une bonne efficacité thérapeu-tique avec un risque hémorragique minimum. Après des recherches à l'aide des approches gène-candidat, les polymorphismes des gènes codant pour le cytochrome P4502C9 (CYP2C9), la vitamine K époxyde réductase (VKORC1) [29] et le cytochrome P4504F2 (CYP4F2) ont été significativement associés à la variabilité de réponse à la warfarine par des approches de génomique (genome-wide) [9][10][11]. Ainsi, les génotypes de CYP2C9, de VKORC1 et de CYP4F2, l'âge et le poids permettent d'expliquer 60,5 % de la variabilité interindividuelle de la dose à l'équilibre de la warfarine [12].…”